PROJECT SUMMARY The scientific goal of this application is to examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with type 1 diabetes mellitus (T1D). Glycemic management of T1D is typified by alternating periods of hyper- and hypoglycemia. Because brain metabolism under usual conditions depends on glucose, acute hypoglycemia leads to immediate complications including impaired cognitive function and a counter-regulatory hormone response. Recurrent hypoglycemia is associated with functional and structural changes in the brain, and contributes to the cognitive decline observed in individuals with diabetes. The state of nutritional ketosis (as distinct from diabetic ketoacidosis) may protect against these acute and chronic complications by providing an alternative fuel for the brain. Studies during hypoglycemia have shown better cognitive function and lower hypoglycemia symptoms in the setting of nutritional ketosis or ketone administration. This physiological benefit may have special relevance for people with T1D who experience hypoglycemia frequently. To date, no mechanistic studies have examined brain effects of nutritional ketosis in T1D; nor have any trials explored the potential practical translation into a relevant clinical setting. To examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with T1D, I propose a randomized mechanistic study using insulin-clamping and neuroimaging. The study will leverage a randomized controlled trial (RCT) concurrent with my K23 award. Thirty-two adolescents and young adults with T1D will receive a very low-carbohydrate diet (5% carbohydrate, 20% protein, 75% fat, expected to cause nutritional ketosis) vs a standard diet (50%, 20% protein, 30% fat). With this rigorously controlled design to provide a strong contrast of brain physiology, I propose to conduct a euglycemic-hypoglycemic insulin clamp and assess activation and connectivity of relevant brain areas by magnetic resonance imaging. Using continuous imaging during a gradual glycemic descent from 90 mg/dl to 50 mg/dl, I will establish the glycemic threshold at which the hypothalamus becomes activated (Aim 1). Using a combination of imaging modalities, I will assess brain activation and connectivity changes during hypoglycemia vs euglycemia (Aim 2). Brain findings will be integrated with physiologic (blood levels of glucose, ketones, free fatty acids, counter regulatory hormones) and behavioral (reaction time, cognitive task performance, hypoglycemia symptoms scale) parameters. Comparison will be made between the 2 diet arms. As a result of these studies, I hope to elucidate whether nutritional ketosis increases, both neurological and behavioral, hypoglycemia tolerance in people with T1D, and to clarify mechanisms linking diet to brain physiology. The research findings will contribute to the understanding of brain metabolism, with direct potential implications to the management of T1D.